The primary goal of the proposed research is to clarify the role cf potassium channels in regulating coronary vascular tone. Such information may be vital to understanding the cellular mechanisms responsible for controlling coronary artery diameter under normal and pathophysiological conditions. The focus of this research plan is on substances thought to open potassium channels in the cell membrane (i.e. BRL 38227, EMD 52692, and RP 49356). Functional and biochemical studies will be performed on porcine isolated coronary arteries. 86Rb efflux will be used as a marker for potassium channel opening activity; the ability of each substance to stimulate 86Rb efflux will be tested in this preparation. Changes in isometric tension will be measured and the ability of these agents to cause relaxation of coronary vascular smooth muscle, in a manner consistent with the opening of potassium channels, will be determined. Potential differences in responsiveness due to the presence of endothelium, the nature of the vasoconstrictor used to induce tone, and the anatomical location (e.g. proximal vs. distal) along the course of the coronary artery will be examined. The inhibitory effects of the potassium channel openers will be compared with other coronary vasodilators and possible synergistic interactions will be studied. Experiments will be performed to investigate several potential mechanisms by which potassium channel openers could impair calcium handling in coronary vascular smooth muscle cells. The specificity of all observed responses will be examined by performing studies in the presence of several known potassium channel blockers. The experiments described herein will provide exciting, new information regarding novel mechanisms for regulating coronary vascular tone. It is anticipated that the knowledge gained from these studies will have important therapeutic implications (e.g. coronary vasospasm), as well as provide additional insight into the cellular mechanisms governing coronary vasomotion.